Corticotropin releasing factor (CRF) is a primary integrator of the stress response and there is evidence that CRF acts as a neurotransmitter or neuromodulator in the brain. The effects of CRF in the brain are mediated by two distinct receptors, CRF1 and CRF2. Activation of CRF receptors leads to an increase in neuronal excitability while administration of peptide CRF antagonists can result in reduced neuronal damage in models of focal and global ischaemia and following excitatory amino acid administration. Although peptide CRF antagonists appear to be neuroprotective, their therapeutic utility is limited by their short half-life and inability to cross the blood-brain barrier. This proposal will examine the neuroprotective ability of novel, non-peptide, CRF1 receptor antagonists following systemic administration of the antagonists. The specific aims are: 1) to screen four CRF1 receptor antagonist lead compounds for their efficacy as neuroprotective agents against excitatory amino acid-induced neurodegeneration; 2) to complete time course and dose-response studies of one lead compound, NBI 27914, in the middle cerebral artery occlusion (MCAo) model of cerebral ischaemia in order to determine optimal parameters for the further examination of the compounds examined in the first specific aim; and 3) to assess the effectiveness of the two most promising compounds from specific aim one in the MCAo model of cerebral ischaemia.